Tishchenko reaction, aldol

The first highly enantioselective cross-aldol-Tishchenko reaction of alkyl aryl ketones 28 and aldehydes was developed by the group of Shibasaki et al. [15]. With a chiral heterobimetallic lanthanide-based catalyst, this reaction was shown to proceed in typically very good enantioselectivity to furnish, after saponification of 

Both (—)-(4R,5R)- or (+)(4S,5S)-2,2-dimethyl-a,a,a, a -tetraphenyl-l,3-dioxolane-4,5-dimethanol (TADDOL) and l,l -bi-2-naphthol (BINOL) ligands were investigated as chiral Ugands in this process to establish an enantioselective aldol-Tishchenko reaction based upon this concept. However, only moderate enantioselectivities of up to 60% ee were obtained [19]. 

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Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

In the aldol-Tishchenko reaction, a lithium enolate reacts with 2 mol of aldehyde, ultimately giving, via an intramolecular hydride transfer, a hydroxy ester (51) with up to three chiral centres (R, derived from rYhIO). The kinetics of the reaction of the lithium enolate of p-(phenylsulfonyl)isobutyrophenone with benzaldehyde have been measured in THF. ° A kinetic isotope effect of fee/ o = 2.0 was found, using benzaldehyde-fil. The results and proposed mechanism, with hydride transfer rate limiting, are supported by ab initio MO calculations. 

The mechanism of the aldol-Tishchenko reaction has been probed by determination of kinetics and isotope effects for formation of diol-monoester on reaction between the lithium enolate of p-(phenylsulfonyl)isobutyrophenone (LiSIBP) and two molecules of benzaldehyde. ". The results are consistent with the formation of an initial lithium aldolate (25) followed by reaction with a second aldehyde to form an acetal (26), and finally a rate-limiting intramolecular hydride transfer (Tishchenko... 

In 1998, Hasanayn and Streitwieser reported the kinetics and isotope effects of the Aldol-Tishchenko reaction . They studied the reaction between lithium enolates of isobu-tyrophenone and two molecule of beuzaldehyde, which results iu the formation of a 1,3-diol monoester after protonation (Figure 28). They analyzed several aspects of this mechanism experimentally. Ab initio molecular orbital calculatious ou models are used to study the equilibrium and transition state structures. The spectroscopic properties of the lithium enolate of p-(phenylsulfonyl) isobutyrophenone (LiSIBP) have allowed kinetic study of the reaction. The computed equilibrium and transition state structures for the compounds in the sequence of reactions in Figure 28 are given along with the computed reaction barriers and energy in Figure 29 and Table 6. 

A short review examines the current status and prospects for the direct asymmetric aldol-Tishchenko reaction, a process which allows for stereocontrol of three con- tiguous chiral centres in three-aldehyde or aldehyde-ketone-aldehyde reactant combinations.139... 

Modern Aldol Reactions contains several pertinent reviews (i) catalytic enantiose-lective aldols with chiral Lewis bases 97 (ii) the aldol-Tishchenko reaction 98 (iii) titanium—enolate aldols 99 (iv) crossed aldols mediated by boron and silicon enolates 100 (v) amine-catalysed aldols 101 and (vi) aldols catalysed by antibodies.102... 

A direct aldol-Tishchenko reaction of aromatic aldehydes with ketones proceeds with stereocontrol of up to five contiguous centres in a chain, using titanium(IV) r-butoxide and cinchona alkaloids.146 A tricyclic transition state is proposed to explain the high (g) degree of stereoselection. 

A syn-2-amino alcohol, complexed with Yb(III), catalyses the aldol-Tishchenko reaction of aliphatic ketones with aromatic aldehydes to give anti- 1,3-diol monoesters with three adjacent stereocentres in high yield, de, and ee.141 ... 

The mixed Tishchenko reaction involves the reaction of the aldol prodnct 113 from one aldehyde with another aldehyde having no a-hydrogens to yield an ester The products were proposed to be formed through an aldol step (equation 33), followed by addition of another aldehyde (equation 34) and an intramolecular hydride transfer (equation 35). However, several aspects of this mechanism need to be clarified. As part of the continuing mechanistic studies carried out by Streitwieser and coworkers on reactions of alkali enolates ", it was found that the aldol-Tishchenko reaction between certain lithium eno-lates and benzaldehyde proceeded cleanly in thf at room temperature". Reaction of the lithium enolate of isobutyrophenone (Liibp) with 1 equiv of benzaldehyde in thf at — 65 °C affords a convenient route to the normal aldol product 113 (R = R" = Ph, R = Me). At room temperature, however, the only product observed after acid workup was the diol-monoester 116, apparently derived from the corresponding lithium ester alcoholate (115, R = R" = Ph, R = Me), which was quantitatively transformed into 116 after quenching. As found in other systems", only the anti diol-monoester diastereomer was formed. 

Mahrwald, R. The aldol-Tishchenko reaction Atool in stereoselective synthesis. Curr. Org. Chem. 2003, 7, 1713-1723. 

Mahrwald, R., Costisella, B. Titanium-mediated aldol-Tishchenko reaction. A stereoselective synthesis of differentiated anti 1,3-diol monoesters. Synthesis 1996, 1087-1089. 

Bodnar, P. M., Shaw, J. T., Woerpel, K. A. Tandem Aldol-Tishchenko Reactions of Lithium Enolates A Highly Stereoselective Method for Diol and Triol Synthesis. J. Org. them. 1997, 62, 5674-5675. 

Abu-Hasanayn, F., Streitwieser, A. Kinetics and Isotope Effects of the Aldol-Tishchenko Reaction between Lithium Enolates and Aldehydes. J. Org. Chem. 1998, 63, 2954-2960. 

Tandem aldol-Tishchenko reactions occur. The highly stereoselective nature of such processes makes them very valuable in the access to diols and triols. 

Fig. 2.17 At the centerpiece of organic chemistry the making of new carbon-carbon bonds in stereoselective fashion using organometallic catalysis, (a) Aldol-Tishchenko reaction [81], (b) Pictet-Spengler reaction [82], (c) Mannich reaction [83], (d) hydroformylation [84],...

Nakajima developed an enantioselective aldol-Tishchenko reaction by using chiral lithium binaphtholate 8, to afford 1,3-diol derivatives with three contiguous chiral centres and high stereoselectivities (Scheme 2.6). Acyclic ketones gave l,2-a ff-l,3-a ff-diols such as 9 via TS-11 and cyclic ketones... 

Scheme 8.9 Domino aldol-Tishchenko reaction developed by Morken et al. [14],...

Mlynarski et al. [16] developed ytterbium-catalyzed enantio- and diastereoselective aldol-Tishchenko reactions of symmetrical dialkyl ketones as enol components for the first time. As chiral ytterbium ligand, they employed the amino alcohol 32, which gave rise to aldol-Tishchenko products such as 33 with up to 86% ee (Scheme 8.10). As documented by control experiments and very similar to the above discussed processes, the rate- and stereo-determining step in this reaction was proven to be the Tishchenko reduction with a rapid pre-retro-aldol equilibrium of the initially formed aldol products. This process may be utilized for reactions of alkyl aryl ketones as well, broadening its scope significantly. 

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